Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease
The etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dih...
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MDPI AG
2023-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/8/2159 |
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| author | Daria A. Belinskaia Polina A. Voronina Denis V. Krivorotov Richard O. Jenkins Nikolay V. Goncharov |
| author_facet | Daria A. Belinskaia Polina A. Voronina Denis V. Krivorotov Richard O. Jenkins Nikolay V. Goncharov |
| author_sort | Daria A. Belinskaia |
| collection | DOAJ |
| description | The etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1<i>H</i>-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the G<sub>s</sub>-protein-coupled serotonin receptors (5-HTR) 5-HT<sub>6</sub>, 5-HT<sub>4</sub> and 5-HT<sub>7</sub> (5-HT<sub>4</sub>R, 5-HT<sub>6</sub>R and 5-HT<sub>7</sub>R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole–carboxamides effectively bind to 5-HT<sub>4</sub>R and 5-HT<sub>7</sub>R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1<i>H</i>-benzimidazole-1-carboxamide hydrochloride (compound <b>13</b>) as the most promising for further experimental development. |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T23:38:34Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-613356f7db1840c6a78090b71bfd43eb2023-11-19T02:37:47ZengMDPI AGPharmaceutics1999-49232023-08-01158215910.3390/pharmaceutics15082159Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s DiseaseDaria A. Belinskaia0Polina A. Voronina1Denis V. Krivorotov2Richard O. Jenkins3Nikolay V. Goncharov4Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, St. Petersburg 194223, RussiaSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, St. Petersburg 194223, RussiaResearch Institute of Hygiene, Occupational Pathology and Human Ecology, Federal Medical Biological Agency, p.o. Kuzmolovsky, St. Petersburg 188663, RussiaLeicester School of Allied Health Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UKSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez 44, St. Petersburg 194223, RussiaThe etiology and pathogenesis of Alzheimer’s disease are multifactorial, so one of the treatment strategies is the development of the drugs that affect several targets associated with the pathogenesis of the disease. Within this roadmap, we investigated the interaction of several substituted 1,3-dihydro-2-oxo-1<i>H</i>-benzimidazol-2-ones with their potential molecular targets: cholinesterases (ChE) and three types of the G<sub>s</sub>-protein-coupled serotonin receptors (5-HTR) 5-HT<sub>6</sub>, 5-HT<sub>4</sub> and 5-HT<sub>7</sub> (5-HT<sub>4</sub>R, 5-HT<sub>6</sub>R and 5-HT<sub>7</sub>R, respectively). A microplate modification of the Ellman method was used for the biochemical analysis of the inhibitory ability of the drugs towards ChE. Molecular modeling methods, such as molecular docking and molecular dynamics (MD) simulation in water and the lipid bilayer, were used to study the interaction of the compounds with ChE and 5-HTR. In vitro experiments showed that the tested compounds had moderate anticholinesterase activity. With the help of molecular modeling methods, the mechanism of interaction of the tested compounds with ChE was investigated, the binding sites were described and the structural features of the drugs that determine the strength of their anticholinesterase activity were revealed. Primary in silico evaluation showed that benzimidazole–carboxamides effectively bind to 5-HT<sub>4</sub>R and 5-HT<sub>7</sub>R. The pool of the obtained data allows us to choose N-[2-(diethylamino)ethyl]-2-oxo-3-(tert-butyl)-2,3-dihydro-1<i>H</i>-benzimidazole-1-carboxamide hydrochloride (compound <b>13</b>) as the most promising for further experimental development.https://www.mdpi.com/1999-4923/15/8/2159Alzheimer’s diseasebenzimidazolonescholinesterasesserotonin receptorsbiochemical analysismolecular docking |
| spellingShingle | Daria A. Belinskaia Polina A. Voronina Denis V. Krivorotov Richard O. Jenkins Nikolay V. Goncharov Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease Pharmaceutics Alzheimer’s disease benzimidazolones cholinesterases serotonin receptors biochemical analysis molecular docking |
| title | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
| title_full | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
| title_fullStr | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
| title_full_unstemmed | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
| title_short | Anticholinesterase and Serotoninergic Evaluation of Benzimidazole–Carboxamides as Potential Multifunctional Agents for the Treatment of Alzheimer’s Disease |
| title_sort | anticholinesterase and serotoninergic evaluation of benzimidazole carboxamides as potential multifunctional agents for the treatment of alzheimer s disease |
| topic | Alzheimer’s disease benzimidazolones cholinesterases serotonin receptors biochemical analysis molecular docking |
| url | https://www.mdpi.com/1999-4923/15/8/2159 |
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